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The list of genes shown to be associated with hearing loss continues to grow, and that's promising news for patients, as each newly identified mutation expands diagnostic opportunities and highlights a potential pathway for future treatment.

One of the latest discoveries came from an international research team led by the University of Cincinnati and Cincinnati Children's Hospital Medical Center. Along with colleagues from the National Institute on Deafness and Other Communication Disorders, Baylor College of Medicine, the University of Kentucky, and other institutions, the team identified genetic mutations responsible for nonsyndromic deafness and Usher syndrome type 1J.

Nonsyndromic deafness accounts for about 80% of genetic hearing loss. Children with Usher syndrome type 1 typically are born profoundly deaf, have severe balance problems, and develop vision problems in early childhood.

Previous studies identified a link between a region on chromosome 15 and hearing impairment in Pakistani families. The new study, published in Nature Genetics (2012;44[11]:1265), identifies the specific gene, called CIB2, responsible for the condition.

The study involved families with children whose hearing loss and/or Usher syndrome was inherited in a recessive manner, meaning that both parents passed along the same mutant gene. Through genetic analysis, the team identified one Turkish and 56 Pakistani families with CIB2 mutations resulting in nonsyndromic hearing loss, and one family with a mutation responsible for Usher syndrome type 1.

“We have identified at least three different mutations in CIB2 that lead to nonsyndromic hearing loss and one mutation causing Usher syndrome,” noted Arnaud Giese, PhD, a study coauthor and research fellow in Cincinnati Children's Division of Pediatric Otolaryngology–Head and Neck Surgery.

CIB2, which encodes a calcium- and integrin-binding protein, is believed to play a role in mechanoelectrical transduction, the process of converting sound energy into an electrical signal that the brain recognizes as sound. Specifically, scientists think the gene may be important in maintaining calcium levels in the sensory cells.

Given that there are many cardiac ischemia and hypertension drugs that work by affecting calcium handling in the muscle cells, “it is possible that one day a similar drug may be used to target a type of Usher syndrome that we described in our study,” Dr. Giese said.

RAPID PROGRESS

Karen P. Steel, PhD, a professor of sensory function at the Wolfson Centre for Age-Related Disease at King's College London, who was not involved in the study, said the team's discovery marks the 11th gene associated with Usher syndrome.

“These genes that can underlie both syndromic and nonsyndromic deafness are particularly interesting because they should tell us something about what it is about the altered function of the protein that causes deafness alone or both deafness and blindness,” she said.

Dr. Steel, who is considered one of the top researchers in the field of hereditary deafness, counts an early discovery among her most significant findings. She was part of a research team that in 1995 identified MYO7A (myosin VIIA), a gene whose mutated form leads to deafness and balance problems in the mouse and Usher syndrome in humans.

Since that time, more than 100 genes have been implicated in various types of hearing loss, both syndromic and nonsyndromic, experts say. Despite rapid progress, many hearing-related genes have yet to be identified.

“I guess that in another 10 years we will know most of the genes associated with deafness,” Dr. Steel said. But identification is just the first step. Understanding how a gene is involved in deafness “takes a lot longer,” she added.

DETECTIVE WORK

It took nearly a decade for a multidisciplinary team of researchers from the University of South Florida (USF) in Tampa, Rochester Institute of Technology in New York, and the House Research Institute in Los Angeles to pinpoint the gene responsible for many cases of presbycusis. Their work, which was published in Hearing Research (2012;294 [1-2]:125), was initiated after a previous study suggested the gene may play a role.

For the study, 687 adults with varying hearing abilities gave blood samples and participated in comprehensive hearing assessments, including tests of speech processing. Their average age was 71. After nine years of study, researchers were able to report an association between the GRM7 (glutamate receptor, metabotropic 7) gene and the kinds of hearing and speech impairments that occur as people age.

GRM7 encodes a protein that is a receptor for L-glutamate. Glutamate is the main neurotransmitter in the auditory system enabling cells in the inner ear to send messages to the brain.

“What we discovered is that the gene that makes this receptor is altered in people who have accelerated age-related hearing loss,” said study coauthor Robert Frisina Jr., PhD, the director of USF's Global Center for Hearing & Speech Research.

IN THE CLINIC

The hope is that efforts to identify genes involved in hearing loss will eventually lead to new therapies.

“With every new gene identified we take a step closer to truly understanding the hearing mechanism and potentially reaching the point where genetic information can be used to prevent hearing loss or to reverse the changes responsible for hearing loss,” said Mary M. Whitaker, AuD, a clinical professor at Idaho State University in Pocatello.

Some treatments may help with symptoms related to syndromic conditions. United Kingdom-based Oxford BioMedica is currently conducting early safety and efficacy trials of an experimental gene-transfer agent to treat retinitis pigmentosa in patients with Usher syndrome type Ib, a form caused by MYO7A mutations. There currently is no Food and Drug Administration-approved treatment for Usher syndrome.

At present, though, knowledge about specific hearing-related genes is being harnessed mainly for diagnostic purposes. In fact, the field of genetic diagnostics is advancing at a remarkable clip with the move toward high-volume sequencing tests that allow screening of multiple genes at a time, at a tiny fraction of what it would cost to sequence the genes one by one.

The University of Iowa's OtoSCOPE, introduced in 2011, tests for 66 genes known to cause nonsyndromic hearing loss, Usher syndrome, and Pendred syndrome.

Identifying the etiology of hearing loss can provide families with useful information, said Kathryn Laudin Beauchaine, audiology coordinator at Boys Town National Research Hospital in Omaha, NE.

“If it is discovered that a child is likely to develop progressive vision impairment, for example, the family might opt to teach the child braille. If progressive hearing loss is a risk or a likelihood with an identified syndrome, the child might be followed more closely for possible hearing loss progression. The family might consider cochlear implants earlier in the child's development.”

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